Plasmacytoid dendritic cells (PDC) represent a unique secretory cell type that plays a critical role in innate immune responses. PDC respond to virus-associated nucleic acids with a massive secretion of type I interferon (IFN), and therefore are often described as natural interferon-producing cells. In addition, PDC are capable of differentiation into conventional antigen-presenting dendritic cells, and of activating a wide range of immune cell types. Because of their IFN-producing capacity, PDC are essential for the control of viral infections, whereas aberrant IFN secretion by PDC appears to be involved in autoimmune diseases. The PDC possess unique cellular and molecular features and gene expression patterns that facilitate their distinct homing and migration pattern, direct recognition of viruses, high-level IFN secretion and differentiation into dendritic cells. However, the molecular mechanisms that regulate lineage commitment, maturation, and function of PDC remain poorly understood. The overall goal of our research is to dissect the regulation of PDC development and function at the molecular level. In preliminary experiments, we identified candidate transcriptional and signaling mechanisms operating in the PDC. In Specific Aim 1, we will analyze the role of basic helix-loop-helix transcription factors in PDC development and maintenance. In Specific Aim 2, we will concentrate on Smad-mediated TGFb superfamily signaling in the PDC lineage. Altogether, these studies would elucidate the genetic network governing PDC development and function, and thus pave the way for immunotherapeutic approaches directed at the PDC. PROJECT NARRATIVE: The study is aimed at molecular and genetic analysis of plasmacytoid dendritic cells (PDC), a unique immune cell type that plays a major role in anti-viral immune responses and in autoimmunity. The elucidation of molecular mechanisms that govern PDC development and function would pave the way for novel therapeutic approaches targeting PDC function in infections and autoimmune diseases.